High-grade perianal dysplasia (PAIN 2-3) occurs with increased frequency in HIV-infected patients. These anogenital skin lesions are frequently diffuse, treatment is associated with significant morbidity, recurrence rates after treatment are high, and invasive cancers may develop. For these reasons, there is a need for better-tolerated and effective therapy. Cidofovir has been reported to have activity against human papillomaviruses (HPV) and to induce regression of HPV-associated lesions when used topically. The primary aims of this clinical trial are to evaluate the efficacy and safety of topical cidofovir 1% for the treatment of PAIN 2-3 in HIV-infected patients. The study will also increase our knowledge of the biology of PAIN 2-3 in HIV-infected patients through exploratory studies evaluating the following aims: 1) To determine the HPV DNA types and HPV strain variants present in PAIN 2-3 and normal perianal tissue and determine if clinical regression is associated with clearance of HPV DNA; 2) To identify the HPV DNA types present in the anal canal and cervix and compare them with the HPV DNA of the perianus to determine if the HPV types associated with the perianal lesions are the same as those infecting the anal canal and cervix; 3) To determine if there are abnormally methylated genes in PAIN 2-3 compared with normal tissue and if these genes are the same or different from those that have been previously identified in anal and cervical dysplasia. Also, to investigate whether methylated genes are changed after treatment with cidofovir; 4) To characterize differences in gene expression in PAIN 2-3 compared with normal perianal tissue, and to examine changes in gene expression in PAIN after exposure to cidofovir with RNA microarray analysis and confirm results with real-time PCR. 5) To evaluate whether pretreatment CD4 count, HIV viral load, lesion size, methylation pattern, and/or HPV type/strain are correlated with the clinical efficacy of topical cidofovir. New anti-retroviral medications have increased the life expectancy of HIV-infected patients, but have not changed the incidence of dysplasias or cancers of the anogenital epithelium. Novel treatments, such as topical cidofovir, may prevent pre-cancerous lesions from developing into cancer in HIV-infected patients.